Fatty acid biosynthesis (FAB) is necessary for the production of bacterial cell walls, and therefore is essential for the survival of bacteria (Magnuson et al., 1993, Microbiol. Rev. 57:522-542). The fatty acid synthase system in E. coli is the archetypal type II fatty acid synthase system. Multiple enzymes are involved in fatty acid biosynthesis, and genes encoding the enzymes fabH, fabD, fabG, acpP, and fabF are clustered together on the E. coli chromosome. Clusters of FAB genes have also been found in Bacillus subtilis, Haemophilus influenza Rd, Vibrio harveyi, and Rhodobacter capsulatus. Examples of FAB genes in B. subtilis include fabD, yjaX, and yhfB (encoding synthase III), fabG, ywpB, yjbW, yjaY, ylpC, fabG, and acpA. The ylpC, fabG, and acpA genes are contained within a single operon that is controlled by the PylpC promoter.
Using genetic and biochemical methods, the targets and mechanisms of action of several inhibitors of the elongation part of the FAB pathway have been identified (FIG. 1). The FAB inhibitor cerulenin inhibits β-ketoacyl-ACP synthase, and the inhibitor thiolactomycin inhibits acetoacyl ACP synthase (Omura, 1981, Meth. Enzymol. 72:520-532; Moche et al., 1999, J. Biol. Chem. 274:6031-6034; and Jackowski et al., 1989, J. Biol. Chem. 264:7624-7629). The FAB inhibitors isoniazid, triclosan, and diazaborine inhibit enoyl-acyl carrier protein reductase (Quemard et al., 1995, Biochem. 34:8235-8241; McMurray et al., 1998, Nature 394:531-532; Heath et al., 1998, J. Biol. Chem. 273:30316-30320; Heath et al., 1999, J. Biol. Chem. 274:11110-11114; Levy et al., 1999, Nature 398:383-384; and DeBoer et al., 1999, Mol. Microbiol. 31:443-450). In Pseudomonas aeruginosa, triclosan has been shown to inhibit the enoyl-acyl carrier protein reductase (FabI), which converts trans-2-enoyl-ACP to acyl-ACP (Hoang and Schweizer, supra). The FAB pathway provides the acyl groups for production of acylated homoserine lactones (HSLs). HSLs are the signaling molecules involved in quorum sensing, i.e., bacterial cell-to-cell signaling, in a wide variety of bacteria. In pathogenic bacteria, such as Pseudomonas, quorum sensing is a mechanism for regulating the expression of virulence factors (Hastings and Greenberg, 1999, J. Bacteriol. 181:2667-2668).